title: Rapid stereoselective hydrolysis of (+)-cocaine in baboon plasma prevents its uptake in the brain: implications for behavioral studies.
abstract: The naturally occurring enantiomer of cocaine, (-)-cocaine, has been previously labeled with 11C on the N-methyl group and used in conjunction with positron emission tomography to show that cocaine is rapidly taken up in the striata of human and baboon brain. In the present study, the behaviorally inactive (+)-cocaine was similarly labeled, with a view to its use for measuring the nonspecific binding of cocaine. No brain uptake was seen, although transport of cocaine into the brain is not expected to be stereoselective. The explanation for the lack of uptake was determined to be very rapid metabolism of (+)-cocaine in the blood. By 30 s after administration of labeled (+)-cocaine, it was undetectable in plasma. In vitro studies demonstrated that (+)-cocaine is 50% debenzoylated to (+)-ecgonine methyl ester within 5 s of exposure to baboon plasma but not to washed erythrocytes. The hydrolysis of (-)-cocaine is at least 1,000 times slower. Serum butyrylcholinesterase (EC 3.1.1.8) appears to be responsible for this hydrolysis, as evidenced by its inhibition by physostigmine and catalysis by commercially available pseudocholinesterase from horse and human blood.
authors.affiliation: Department of Chemistry, Brookhaven National Laboratory, Upton, NY 11973.
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: R R
authors.initials: RR
authors.lastname: MacGregor
authors.forename: J S
authors.initials: JS
authors.lastname: Fowler
authors.forename: A P
authors.initials: AP
authors.lastname: Wolf
authors.forename: S L
authors.initials: SL
authors.lastname: Dewey
authors.forename: D J
authors.initials: DJ
authors.lastname: Schlyer
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000528:radiation effects; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000097:blood / Q000378:metabolism*; D006868:Hydrolysis; D010215:Papio; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed
chemical_list: D003042:Cocaine